This area of investigation began with the demonstration of monoclonal anti-MAG antibodies in patients with mixed motor-sensory polyneuropathies occurring in association with IgM paraproteinemia. It was subsequently demonstrated that these anti-MAG antibodies were all directed toward carbohydrate epitopes in MAG and cross-reacted with l9 to 28 kD glycoproteins of PNS myelin and a sphingoglycolipid, sulfate-3-glucuronyl paragloboside (SGPG). Although all these human anti-MAG antibodies have similar specificities since they react with the same family of glycoconjugates in nerve, experiments with chemically modified derivatives of SGPG have revealed differences in fine specificities. Some of the human antibodies and the related HNK-1 antibody absolutely require the sulfate for reactivity, others require the free carboxyl group of glucuronic acid, whereas still others will react if either one or the other of the two negatively charged groups is present. The fine specificity of the anti-MAG antibodies may affect the clinical presentation in these patients. Our research in recent years has emphasized antibodies to GM 1 ganglioside in patients with motor nerve disorders. Four patients with multifocal motor neuropathy were found to have high titers of polyclonal antibodies reacting with GM 1 ganglioside. The fine specificities of these antibodies also differed in the individual patients as revealed by identification of different cross reacting gangliosides. Since GM 1 was the only common antigen in these patients, GM 1 may be the pathogenically significant target antigen in motor nerves. Although these findings reveal a strong correlation between the occurrence of antibodies to GM 1 and one type of motor nerve disorder, we did not find high levels of antibodies to GM 1 in motor neuron disease or amyotrophic lateral sclerosis. Preliminary results have revealed moderately elevated antibodies to gangliosides in some cases of adrenoleukodystrophy which may play a role in variable secondary autoimmune aspects of this genetic disease caused by a defect in the peroxisomal degradation of saturated, very long chain fatty acids. Finally, it should be emphasized that our work and that of others indicates that serum antibodies in patients with neurological diseases should be analyzed both qualitatively by TLC overlay and quantitatively by ELISA, since the pathogenic significance of antibodies to glycolipids appears to depend both on their specificity and titer.